Pour-on formulations

ABSTRACT

A non-irritant topically acceptable carrier selected from the group consisting of: a) i) at least one of tripropylene glycol methyl ether and dipropylene glycol methyl ether, and ii) at least one of alcohol, wool grease and propylene glycol, wherein (i) is present in an amount of at least about 60% wt of the carrier; b) i) at least one of octyl palmitate, octyl stearate and glyceryl tri caprylate/caprate, and ii) at least one of dioctyl succinate, isopropyl myristate, cetearyl octanoate, propylene glycol 2 myristyl ether propionate, isopropyl palmitate, isopropyl laurate, isocetyl stearate, oleic acid and methyl oleate, and optionally including iii) at least one of alcohol, wool grease and propylene glycol, wherein (ii) is present in an amount of up to about 40% wt of the carrier; and c) i) at least one of octyl palmitate, octyl stearate and glyceryl tri caprylate/caprate, and ii) at least one of alcohol, wool grease and propylene glycol, wherein (i) is present in an amount of at least about 60% wt of the carrier.

The present invention relates to non-irritant carriers or carrier blendssuitable for use in pour-on formulations, the formulations themselvesand to the use of those pour-on formulations in the control of externalparasites in animals of agricultural worth including sheep, cattle,pigs, goats, camelids, horses and other small ruminants.

Animals of agricultural worth, such as sheep, cattle, horses, goats,pigs, other ruminants and camelids, are almost invariably subject to theactivity of ectoparasites such as flies, ticks, lice and fleas. Suchexternal parasites irritate the animals and can cause economic losses inthe forms of poor quality hide, wool or sheep skin, reduced weight gainand even death as a result of the animal carrying harmful parasites.

It has long been common practice to control external parasites on sheep,cattle and other animals including goats, pigs and horses by thelocalised topical application of a pour-on formulation containing anactive insecticide/parasiticide and a carrier/vehicle. A pour-onformulation is typically liquid and is usually applied to the exteriorof an animal as a line or a spot, which then acts to protect theexternal surface of the animal against external parasites such as lice,keds, mites, ticks and flies.

Ideally, when the formulation is applied topically to a localised area,the ectoparasiticide migrates over the surface of the animal to protectits whole external surface area.

The carrier (also referred to herein as ‘vehicle’) present in suchpour-on formulations is formulated to achieve good spread around theskin and/or penetration of the epidermis of the animal. To date,commercial pour-on formulations are suspensions, emulsifiableconcentrates or solutions and are often comprised of at least oneorganic solvent. Solvents commonly used as carriers in such pour-onformulations include propylene glycol, paraffins, isoparaffins,aromatics, isopropyl myristate (IPM), glycol ethers, and alcohols suchas n-propyl alcohol. U.S. Pat. No. 4,672,072 discloses a non-aqueouscarrier comprising one or more organic solvents such as xylene, toluene,cyclohexanone and a glycol—such as ethylene glycol, polyethyleneglycols, polypropylene glycols, propylene glycol, ethyleneglycol-propylene glycol copolymers and alkyl ethers thereof. A preferredsolvent system disclosed in U.S. Pat. No. 4,672,072 comprises 30–70 wt %xylene, 20–40 wt % cyclohexanone and 5–25 wt % vegetable oil. U.S. Pat.No. 5,045,536 discloses a pour-on formulation in which the solventsystem comprises 80–98% w/v of a non-volatile oil and 2–20% w/v of avolatile silicone.

Unfortunately, the solvent systems utilised as carriers/vehicles incommercially available pour-on formulations may result in some form oftissue reaction which leads to discomfort to the animal and in manycases, damage to the hide, sheepskin or fleece and resultant economicloss. In particular, some breeds of sheep such as the Merino have verysensitive skins which react to the solvent systems in some commerciallyavailable pour-on formulations. For example, aromatics such as xyleneand the paraffins produce tissue reactions such as dryness, redness andcracking of the skin.

U.K. Patent GB 2 110 091 B attempts to address the problems of skinreactions in sheep treated with pour-on formulations by formulating acomposition in which the carrier/vehicle comprises a first solventselected from the group consisting of alkoxylated C₁–C₄ alcohols and asecond solvent selected from the group consisting of di (C₁–C₆ alkyl)esters of C₂–C₆ dicarboxylic acids or C₂–C₆ dihydric alcohols and C₂–C₆carboxylate esters of alcohol alkoxylates. However, sensitive animalhide can still react adversely to such formulations.

Similarly, European Patent Publication No. 0 120 286 Bl addresses theirritancy or toxicity caused to animals by solvent systems in pour-onformulations by providing an active ectoparasiticide in a glycol orglycerol ester of a C₈–C₁₀ fatty acid. However, such oil-basedformulations can still cause adverse epidermal reactions in animalstopically treated with such formulations.

European Patent Publication No. 0 137 627 Bl discloses a pour-onformulation in which the active is an endoparasticide and the carriercomprises at least one saturated aliphatic ester of a mono alkyl etherof a mono- or poly-alkylene glycol such as 1-ethoxyprop-2-yl acetate and2-(n-butoxy)ethyl butyrate. While the specification claims that suchformulations are free from adverse skin reaction in treated sheep orcattle, it is noted that adverse epidermal reactions can still beobserved, particularly in sheep with sensitive skin.

Accordingly, prior art pour-on formulations—even those promoted asnon-irritant—have been found by the present inventors to cause pain andhide damage, and fleece damage in the case of sheep or other fleecebearing animals. Such formulations cause skin damage especially insheep, which have very thin skin and are acutely susceptible to chemicalskin damage.

Additionally, with conventional pour-on formulations 95–98% of theapplied active ingredient remains at the site of application bound tothe animal's fleece or hair, which results in a lack of efficacy.

This invention provides non-toxic and non-irritant carriers that can beused to prepare improved pour-on ectoparasiticidal formulations. Theinvention also provides these improved formulations, which areespecially beneficial because they can be topically applied to animalsof agricultural worth to control ectoparasites without causing adverseepidermal reaction in the animals. The invention also provides a methodof controlling ectoparasites in an animal of agricultural worth bytopically applying one of these non-irritant pour-on ectoparasiticidalformulations on the animal.

The word ‘carrier’ is used throughout the present specification toinclude carrier blends, that is mixtures of more than one substance.

The term “controlling” as used in this specification refers topreventing, ameliorating or eradicating the target ectoparasite.

Certain acronyms and abbreviations used throughout this specificationare commonly used in this art and have the following meanings:

-   -   The term “Alcohol” refers to benzyl alcohol, propyl alcohol,        diacetone alcohol or other suitable alcohol;    -   COI is a blend of isopropyl myristate and cetearyl octanoate,        which are branched chain esters; it acts as an emollient and        spreading agent;    -   DB is diethylene glycol n-butyl ether;    -   DPM is dipropylene glycol methyl ether;    -   GTCC is glyceryl tri caprylate/caprate, which is an excellent        carrier or vehicle for active agents;    -   ICS is isocetyl stearate, which can be used as an emollient,        lubricant and spreading agent;    -   IPM is isopropyl myristate, which has excellent spreading and        emollient properties;    -   IPL is isopropyl laurate;    -   IPP is isopropyl palmitate;    -   OP is octyl palmitate or 2-ethylhexyl palmitate, which is an        excellent lubricant;    -   OS is octyl stearate or 2-ethylhexyl stearate, which is also a        lubricant;    -   OSU is dioctyl succinate or di-2-ethylhexyl succinate, which        promotes wetting and spreading of lipophilic substances onto the        skin;    -   PG is propylene glycol;    -   PMP is, which spreads rapidly and promotes wetting of other        material;    -   SC is a suspension concentrate;    -   TPM is tripropylene glycol methyl ether; and    -   WG is wool grease.

In a first aspect, the invention provides a non-irritant topicallyacceptable carrier selected from the group consisting of:

-   -   a) i) at least one of TPM and DPM, and    -   ii) at least one of alcohol, WG and PG, wherein (i) is present        in an amount of at least about 60% wt of the carrier;    -   b) i) at least one of OP, OS and GTCC, and    -   ii) at least one of OSU, IPM, COI, PMP, IPP, IPL, ICS, oleic        acid and methyl oleate, and optionally including    -   iii) at least one of alcohol, WG and PG, wherein (ii) is present        in an amount of up to about 40% wt of the carrier; and    -   c) i) at least one of OP, OS and GTCC, and    -   ii) at least one of alcohol, WG and PG, wherein (i) is present        in an amount of at least about 60% wt of the carrier.

In a second aspect, the invention provides a non-irritant pour-onformulation for controlling an external parasite in an animal ofagricultural worth, said formulation including an ectoparasiticidalamount of an active agent and a topically acceptable carrier of thefirst aspect of the invention.

A third aspect of this invention provides a method of controlling anexternal parasite in an animal of agricultural worth, said methodincluding topically applying an ectoparasiticidally effective volume ofa pour-on formulation according to the second aspect of the invention toa localised area of the external surface of the animal.

Another aspect of this invention relates to the use of a carrier of thefirst aspect in a non-irritant pour-on formulation for controlling anexternal parasite in an animal of agricultural worth wherein theformulation also includes an effective amount of an ectoparasiticidalagent.

The invention is predicated upon a novel approach to developing carrierssuitable for use in non-irritant and non-toxic pour-on formulations thatare to be used for animals of agricultural worth, such as sheep, cattle,horses, goats and pigs. This approach involved determining the effectsof a potential pour-on ingredient on the skin using a histopathologicalmethodology rather than relying on clinical observation. Such ahistopathological approach has resulted in the significantly improvedpour-on formulations of this invention.

The carriers of the first aspect of this invention have severaladvantages. They are non-irritant and effective. They also have asatisfactory freezing point, suitable viscosity and are cost effective.They easily dissolve any active agent, are easy to use and providesuperior operator safety.

The formulations prepared using these carriers (or vehicles) represent agreat advance over currently available pour-on formulations which havebeen developed upon an ad hoc basis. Such a histopathological approachhas allowed for the identification and elimination of ingredients(including those used in current pour-on formulations) that causeskin/hide damage on a pathological level and also has allowed for theaccurate determination of what percentage of an irritant ingredient willnot cause damage.

Further, the carriers and formulations of this invention promote thespread of active agent around the body and hence increase efficacyagainst ectoparasites which can be present on any part of the body.

Finally, the formulations of this invention require the presence of lessactive agent, thereby reducing wool and tissue residues andenvironmental contamination.

One preferred embodiment of the first aspect of this invention is anon-irritant, topically acceptable carrier selected from the groupconsisting of:

-   -   a) i) at least one of TPM and DPM, and    -   ii) at least one of alcohol, WG and PG, wherein (i) is present        in an amount of at least about 60% wt of the carrier; and    -   b) i) at least one of OP, OS and GTCC, and    -   ii) at least one of OSU, IPM, COI, PMP, IPP, IPL, ICS, oleic        acid and methyl oleate, wherein (ii) is present in an amount of        up to about 40% wt of the carrier.

In carrier (a), solvent (i) is typically present in an amount of atleast about 70% wt of the carrier.

When (a)(ii) is an alcohol, it is typically benzyl alcohol or diacetonealcohol.

An example of carrier (a) is TPM/alcohol where TPM is present in anamount of at least about 60% wt of the carrier. A particularly suitableTPM/alcohol carrier is TPM/benzyl alcohol. Typically, a TPM/alcoholcarrier is formulated having a TPM:alcohol ratio in the range of60–95:40–5, and more typically 80:20.

In carrier (b), substance (ii) is typically present in an amount of upto about 30% wt of the carrier.

Examples of carrier (b) are: OP or OS/IPM/OSU where the combined amountof IPM and OSU is up to about 40% wt of the carrier; and GTCC/IPM/COIwhere the combined amount of IPM and COI is up to about 40% wt of thecarrier. When the carrier is OP/IPM/OSU, the preferred ratio is a rangeof OP:IPM:OSU of 60–90:20–5:20–5, most preferably 70:15:15. When thecarrier is a combination of GTCC/IPM/COI, the preferred ratio ofGTCC:IPM:COI is in a range of 60–90:20–5:20–5, preferably 70:15:15.

Optionally, carrier (b) can include: iii) at least one of alcohol, WGand PG.

One embodiment of the second aspect of the invention, i.e., a pour-onformulation for control of an external parasite in an animal ofagricultural worth, is a formulation that includes:

-   -   (a) from 0.1 to 40% by weight of at least one active agent        selected from the group consisting of synthetic pyrethroids,        organophosphates, macrocyclic lactones        (avermectins/milbemycins), benzoylphenylureas (and other insect        growth regulators) and spinosyns; and    -   (b) from 60–99.9% by weight of a carrier of the first aspect of        the invention.

More specifically, this embodiment provides a pour-on formulation forcontrol of an external parasite in an animal of agricultural worth, saidformulation including:

-   -   (a) from 0.1 to 40% by weight of at least one active agent        selected from the group consisting of synthetic pyrethroids,        organophosphates, macrocyclic lactones        (avermectins/milbemycins), benzoylphenylureas (and other insect        growth regulators) and spinosyns; and    -   (b) from 60–99.9% by weight of a carrier selected from the group        consisting of (1) TPM/alcohol, wherein the TPM is present in an        amount of at least 60% by weight of the carrier; (2) OP/IPM/OSU        wherein the combined amount of IPM/OSU is at least 40% by weight        of the carrier; and (3) GTCC/IPM/COI wherein the combined amount        of IPM/COI is at least 40% by weight of the carrier.

The pour-on formulations of this invention can be in the form of aliquid, powder, emulsion, foam, paste, aerosol, ointment, salve or gel.Typically, the pour-on formulation is liquid.

These pour-on formulations can be effectively applied to sheep, cattle,goats, other ruminants, camelids, pigs and horses. The formulations areparticularly suitable to be applied to sheep, especially short woolsheep.

The pour-on formulations are applied locally to the external surface ofan animal. Although they can be applied at any time, certain regimensare preferable. For example, when the formulations are applied to sheep,they are typically applied within 24 hours after shearing. The sheep arethen usually treated each year after shearing. Fibre animals such asgoats and camelids are also treated after shearing. Cattle are treateddepending on the pest concerned, such as in autumn/winter for lice andin summer for flies.

The pour-on formulation is typically applied by pouring in one orseveral lines or in a spot on the dorsal midline (back) or shoulder ofan animal. More typically, the formulation is applied by pouring italong the back of the animal, following the spine. The formulation canalso be applied to the animal by other conventional methods, includingwiping an impregnated material over at least a small area of the animal,or applying it using a commercially available applicator, by means of asyringe, by spraying or by using a spray race.

An effective amount of the pour-on formulation for topical applicationwill depend on several factors, e.g. the animal being treated, theactive agent in the formulation, and the specific formulation beingused. Generally, the formulation should provide about 0.1–2000 mg of theactive agent/kg of animal body weight.

The effective amount of formulation will vary depending on the animalbeing treated. For example, when the formulation is to be applied to acow, it should provide about 100–2000 mg of the active agent. When it isto be applied to a sheep, it should provide about 20–1000 mg of theactive agent.

The effective amount of active (ectoparasiticidal) agent in theformulation will depend on both the agent and the carrier. Examples ofpreferred amounts of active agents (per kg of animal body weight) are:about 300 mg of spinosad or 100 mg of ivermectin or 600 mg ofbenzoylphenylurea or 80 mg of zeta-cypermethrin, when these agents areformulated in OP/IPM/OSU or TPM/alcohol or GTCC/IPM/COI.

A pour-on formulation of this invention is generally formulated suchthat the active agent is present in a concentration of about 0.1–20%weight/volume, preferably about 0.5 to 5%, depending on the potency ofthe active agent. Typically, the formulation will contain one or more ofthe preferred active agents in the following concentrations(weight/volume):

-   -   zeta-cypermethrin: about 0.5%;    -   ivermectin: about 0.6%;    -   hexaflumuron: about 4–5%; and    -   spinosad: about 2%.

Typically, only a small volume of the pour-on formulation, such as inthe order of 1–80 mL, is required in order to be effective against theexternal parasites. For larger animals such as cattle, a volume of 10–60mL is preferred; and for smaller animals such as sheep, a volume of 5–20mL is suitable.

In the pour-on formulations of this invention, theactive/ectoparasiticidal agent can be a singleinsecticidal/ectoparasiticidal compound or a combination of two or moreinsecticidal/ectoparasiticidal compounds. The active agent is typicallyselected from the group consisting of spinosyns, synthetic pyrethroids,macrocyclic lactones, diamidides (formamidines) such as amitraz,thiazoles, dursban, carbamates, benzimidazoles, fipronil, imidacloprid,triazines, water-insoluble organo-phosphate compounds, propoxur,cabaryl, maldison, dimethoate, rotenone, piperonyl butoxide, Bacillusthuringensis, ronnel, crufomate, benzoylphenylureas and other insectgrowth regulators (IGR) such as hexaflumuron or insect developmentinhibitors (IDI), or related juvenile insect hormone analogues,including cyromazine and dicyclanil.

A particularly useful spinosyn is spinosad.

Examples of synthetic pyrethoids are cyhalothrin, bioresmethrin,bifenthrin, pyrethrins, permethrin, biopermethrin, phenothrin,alphamethrin, barthrin, deltamethrin, phthalthrin, cypermethrin,dimethrin, flumethrin, resmethrin, fluvalinate, allethrin, cismethrin,cyfluthrin, indothrin, cyphenothrin, cyclethrin, tetramethrin,tralomethrin, sumithrin, tralocythrin, fenpropanate and fenvalerate.Particularly useful pyrethrins are alpha-cypermethrin andzeta-cypermethrin.

Examples of macrocyclic lactones are ivermectin, abamectin, moxidectin,doramectin, eprinomectin, and milbemycin.

Examples of water-insoluble organo-phosphate compounds aretetrachlovinphos, chlorpyriphos methyl, pyrimiphos methyl,chlorpyriphos, diazinon, trichlorphos, fenchlorphos, coumaphos,crotoxyphos, chlofenvinephos, dichlofenvinphos, dichlorfenthion,quinthiophos, propetamphos, famphur, bromophos ethyl, ethion, anddioxathion.

Examples of benzoylphenylureas are lufenuron, diflubenzuron, triflumuronand fluazuron.

More typically, the active agent is selected from the group consistingof spinosad, zeta-cypermethrin, ivermectin and hexaflumuron.

The carriers of this invention are non-aqueous. The active agent issuspended, dissolved or dispersed in the carrier. The carrier promotesthe penetration of the active agent through the animal's coat and spreadof the agent over the skin.

In addition to the carrier and the active agent, the pour-onformulations of this invention can also include one or more additionalingredients. Examples of suitable additional ingredients are stabilizerssuch as antioxidants, spreading agents, preservatives, adhesionpromoters, active solubilisers such as oleic acid, viscosity modifiers,UV blockers or absorbers, and colourants. Surface active agents,including anionic, cationic, non-ionic and ampholytic surface activeagents, can also be included in these formulations.

The formulations of this invention typically include an antioxidant,such as BHT (butylated hydroxytoluene). The antioxidant is generallypresent in amounts of at 0.1–5% (wt/vol).

Some of the formulations require a solubilizer, such as oleic acid, todissolve the active agent, particularly if spinosad is used.

Common spreading agents used in these pour-on formulations are: IPM,IPP, caprylic/capric acid esters of saturated C₁₂–C₁₈ fatty alcohols,oleic acid, oleyl ester, ethyl oleate, triglycerides, silicone oils andDPM.

The pour-on formulations of this invention are prepared according toknown techniques. Where the pour-on is a solution, theparasiticide/insecticide is mixed with the carrier or vehicle, usingheat and stirring where required. Auxiliary or additional ingredientscan be added to the mixture of active agent and carrier, or they can bemixed with the active agent prior to the addition of the carrier. If thepour-on is an emulsion or suspension, these formulations are similarlyprepared using known techniques.

A general procedure for preparing these formulations involves thesesteps:

-   -   1) Weigh out the desired weight of technical active agent;    -   2) Add 0.1–1% w/v BHT or other appropriate antioxidant;    -   3) If the agent is spinosad, add oleic acid (4 times the weight        of spinosad used), and dissolve by stirring;    -   4) Make up the desired volume by adding a carrier of this        invention;    -   5) Mix by stirring and gently heating if necessary—to up to 50        degrees C.; and    -   6) Dispense into impervious containers and protect from light.

This invention further provides a method of controlling an externalparasite in an animal of agricultural worth, said method includingtopically applying an ectoparasiticidally effective volume of a pour-onformulation according to the second aspect of the invention to alocalised area of the external surface of the animal. The targetexternal parasites include lice, ticks, mites, biting flies, carnivorousflies and fleas. Animals of agricultural worth include cattle, sheep,goats, pigs, horses, camelids and other ruminants.

More specifically, the method of this invention can be used on sheep: tocontrol ked (Melophagus ovinus), chewing louse (Bovicola ovis), suckinglouse (Linognatus pedalis, L. africanus, L. stenopsis), sheep scab mite(Psoroptes ovis), itch mite (Psorergates ovis), mange mite (Chorioptesovis), screw worms (Cochliomyia spp., Chrysomya sp., Wohlfahrtia spp.),ticks (Boophilus spp., Ixodes spp., Haemophysalis spp., Ambylomma spp.,Dermacentor spp., Hyalomma spp., Rhipicephalus spp.), nasal bot flies(Oestrus ovis) and blowflies (Lucilia, Calliphora, Phormia, Protophormiaspp.);

-   -   on goats: to control chewing louse (Bovicola limbata, B.        crassiceps, B. caprae) and sucking louse species (Linognathus        spp.);    -   on camelids: to control chewing lice (Bovicola breviceps);    -   on cattle: to control sucking louse (Linognathus vituli,        Haematopinus eurysternus, Solenopotes capillatus) and chewing        louse (Bovicola bovis), flies (e.g., Musca domestica, Haematobia        irritans, Stomoxys calcitrans), screw worms (Chrysomya bezziana,        Cochliomyia hominivorax), midges, mosquitos, mites (Chorioptes        bovis, Sarcoptes bovis, Psorpotes ovis, Demodex bovis), and        ticks (Boophilus spp, Ixodes spp, Haemophysalis spp, Amblyomma        spp, Dermacentor spp. Hyalomma spp, Rhipicephalus spp, Otobius        megnini);    -   on horses: to control ticks, mites (Chorioptes equi, Psoroptes        equi, Sarcoptes equi, Demodex equi), chewing and sucking lice        (Bovicola equi, Haematopinus asini), fleas, Dipteran species        (Culicoides spp, Simulium spp and other flies); and    -   on pigs: to control ticks, mites (including Sarcoptes suis,        Demodex suis), lice (Haematopinus spp), fleas and Dipteran fly        species.

The formulation is applied to the dorsal midline of the animal, from thepoll to the base of the tail. Preferably, the formulation is appliedusing an applicator, usually a self-filling dosing gun with a nozzle todispense a narrow or wide band or lines of formulation along the back.The formulation is applied at 0.2 to 1 mL per kilogram of body weight orunit of surface area. Alternatively, a set volume is applied to eachbodyweight class, e.g., 10 mL for sheep or animals less than 30 kg, 15mL for animals weighing 31–50 kg, and 20 mL for animals weighing 51+kg.In larger animals, for example in cattle, a typical volume would be 30mL for animals less than 250 kg, 45 mL for animals weighing 250 to 400kg and 60 mL for animals of 400+kg in weight. The formulation can alsobe applied from other containers or vessels as required.

Sheep and other fibre producing animals should be treated within 24hours after shearing or fibre collection. Cattle, horses and otheranimals should be treated so as to ensure maximum impact on the pest tobe controlled. For example, cattle should be treated for lice control inautumn and/or winter. Nuisance or biting fly treatment is applied whenflies begin to cause irritation. This invention is illustrated in anon-limiting manner by reference to the following Examples.

EXAMPLE 1 Pour-On Carrier/Vehicle Sheep Skin Irritation Studies

Studies were conducted to investigate and characterise the changesoccurring in Merino sheep skin following the application of a range ofcandidate pour-on formulation components in order to discern safecarriers. Chemicals, emollients, wool grease derivatives and a widerange of formulations were applied (in 1 mL volumes) to each of 18 siteson the back and flanks of 15 recently shorn Merino sheep.

In the first study, skin samples were collected at necropsy 3½weeksafter application. In subsequent studies, skin samples were collected 2weeks after application. Standard haematoxylin and eosin stainedsections were prepared from each piece of treated skin. A histologicalscoring system was devised to allow comparison of treatments. Each skinwas assessed for the degree of hyperkeratosis, acanthosis andinflammatory cell infiltrate of the superficial dermis and given arating score from 0–15. A score of 0=no change through to a score of 15for very severe damage. Normal skin scored 2–4, >4 was abnormal and >7was very abnormal. Treatments yielding a score

4.5 were considered safe.

Table 1 summarizes the results of these studies.

TABLE 1 Mean skin irritation scores Chemical Score PMP 9 cetearyloctanoate 4.3 IPM 8 OP 3.3 OSU 4.8 GTCC 2 lanolin oil/IPM 7.5 (80:20)GTCC/IPM (80:20) 2.5 OP/IPM (80:20) 2.5 GTCC/COI (80:20) 3 OP/OSU(80:20) 4.5 DB 7 DPM 4 TPM 3 Diacetone alcohol 2 TPM/diacetone alcohol2.5 (80:20) OP/IPM/OSU (70:15:15) 3.2 TPM/benzyl alcohol 2.7 (80:20)untreated 2.5 @

A small experiment was conducted to investigate the pathology over timefollowing application of IPM. It was applied to 2 separate sites on 1sheep on 1, 2, 4, 7, 10 and 14 days before slaughter.

These studies showed that, despite careful daily observation of theskin, some chemicals caused severe histological dermatitis in theabsence of grossly observable changes. IPM caused severe dermatitis.Adding small percentages of other emollients or wool grease failed tomake IPM non-irritant. Reducing the IPM percentage to 20% could yield anon-irritant formulation as long as the other components werenon-irritant. Several other excipients were also highly irritant—such asPMP, C8–C10 methyl esters, methyl oleate, DB, 2-octyl-dodecanol andpropylene glycol dicaprylate dicaprate. Other excipients and mixtures ofexcipients caused mild to moderate dermatitis—such as cetearyloctanoate, DPM, propoxy 15 stearyl alcohol, ICS and OSU. Some mixtureswere non-irritant—such as OP/IPM (80:20); GTCC/OP (80:20); OP/IPM/OSU(70:15:15); GTCC/IPM/COI (70:15:15); TPM/benzyl alcohol (80:20) andseveral mixtures incorporating wool grease derivatives. GTCC, OP,diacetone alcohol, liquid wool grease, lanolin oil, and TPM werenon-irritant.

A commercial formulation of deltamethrin in cyclohexane caused moderatedermatitis. This formulation was reported to cause scab formation on theskin, leading to damage detectable in tanned wool skins (Britt, Cotton,Trask and Pitman, 1984, Aust vet J, 61, 329–330). The pathologydescribed in that paper was similar in type and pattern to that seenassociated with the same formulation in these studies, but was milderthan the severe dermatitis associated with several vehicles investigatedin these studies.

Examples 2–11 describe in vivo formulation comparison and efficacystudies.

Trials were conducted to assess the comparative efficiency of certainpour-on formulations of this invention and commercially availablepour-on formulations in the control of external parasites in sheep.

EXAMPLE 2 Evaluation of Wool Grease Formulations and IPM for the Controlof Bovicola ovis using Zeta-Cypermethrin and Spinosad

The purposes of this study were to evaluate wool grease as a formulationto deliver spinosad, to determine the dose required to kill 100% of licein sheep and to evaluate the suitability of the formulation to deliverzeta-cypermethrin, compared with an isopropyl myristate (IPM)formulation.

Sheep were heavily infested with the highly synthetic pyrethroid (SP)resistant, Hartley strain of lice. Sheep were shorn, lice counted andsheep allocated to ten groups of six sheep, each divided into threegroups of two per treatment. All sheep were treated at the rate of 2 mLof test formulation/10 kg of body weight. Treatments were, respectively:wool grease only; 2 mg/kg deltamethrin and 4 mg/kg alphacypermethrin incommercial formulations; spinosad in wool grease at 0.08 mg/kg, 0.4mg/kg, 2 mg/kg and 10 mg/kg; zeta-cypermethrin in wool grease at 0.66mg/kg and 2 mg/kg; and spinosad in IPM at 0.4 mg/kg. Lice numbers werecounted weekly for eight weeks.

At eight weeks: 2 mg/kg deltamethrin gave 8% efficacy; 4 mg/kgalphacypermethrin gave 9% efficacy; 0.66 mg/kg zeta-cypermethrin gave 0%efficiacy; 2 mg/kg zeta-cypermethrin gave 43% efficiacy; 0.08, 0.4, 2and 10 mg/kg spinosad in wool grease gave 42%, 54%, 98% and 99.9%efficacy, respectively; and 0.4 mg/kg spinosad in IPM gave 85% efficacy.

There were no significant differences in efficacy at eight weeks betweenzeta-cypermethrin in wool grease and deltamethrin and alphacypermethrinin the commercial pour-ons tested; however, zeta-cypermethrin (2 mg/kg)in wool grease gave better lice control than the commercial pour-ons forthe first 5 weeks. Spinosad in IPM gave better control of sheep licethan spinosad in the wool grease gave at comparable dose rates.

EXAMPLE 3 Evaluation of Spinosad in a Variety of Carriers as a Pour-OnFormulation for the Control of Bovicola ovis on Sheep

The aim of this study was to select the most efficacious of a range ofeight formulations that were selected on the basis of safety, physicalproperties, efficacy, cost and theories of dermal insecticide spread.

Each formulation was prepared to provide spinosad at a dose of 0.4 mg/kgand applied at a rate of 1 mL/5 kg of body weight. Groups of lousy sheephoused indoors (6 sheep per group) were treated with spinosad formulatedin these carriers: IPM containing 0.6% oleic acid (IPM), GTCC/IPM/COI(70:15:15), OP/IPM/OSU (70:15:15), TPM/WG/GTCC (60:20:20), OP/IPM(80:20), TPM/OSU (80:20), GTCC/OP (80:20) and an aqueous formulation.

Five of the formulations, IPM, GTCC/IPM/COI, OP/IPM/OSU, TPM/WG/GTCC andthe aqueous formulation, all gave about 90% efficacy by the end of thestudy. OP/IPM was inferior to the others and was eliminated. TPM/OSU andGTCC/OP were also somewhat less effective than the rest. The TPM/WG/OSUformulation was eliminated because WG-containing formulations causedirty discolouration of the wool in sheep run outdoors. IPM alone wasnot a practical formulation due to skin irritation.

The best formulations, in order of cost from cheapest to most expensive,were: aqueous, OP/IPM/OSU and GTCC/IPM/COI.

EXAMPLE 4 Determination of the Therapeutic Efficacy and Dose Titrationof Spinosad in a Pour-On Formulation for the Control of Bovicola ovis onSheep

This study was carried out to select the dose of spinosad required toeradicate sheep body lice when applied as a pour-on in OP/IPM/OSU(70:15:15) containing 5% oleic acid, and to compare the efficacy ofspinosad at 0.4 mg/kg in a suspension concentrate (SC) formulationapplied as a pour-on with that of the pour-on organic solventformulation. The spinosad formulations were applied at 1 mL/5 kg and at0, 0.2, 0.4, 0.8, 1.6 and 3.2 mg/kg to 6 groups of 6 recently shornsheep that were housed outdoors for 6 weeks.

The results observed with the OP/IPM/OSU/oleic acid formulation aresummarized in Table 2:

TABLE 2 Comparison of Efficacy of Various Dosage Levels of SpinosadAdministered in an OP/IPM/OSU Pour-On Formulation Spinosad DosageEfficacy (%) at (mg/kg) Day 41 0.2 37 0.4 46 0.8 78 1.6 37 3.2 93 In theSC formulation spinosad at 0.4 mg/kg gave 65% efficacy.

EXAMPLE 5 Diffusion of ¹⁴C-Zeta-Cypermethrin on Sheep Skin in a Varietyof Carriers

This study compared the amount and rate of diffusion of ¹⁴C-labelledzeta-cypermethrin from the dorsal midline of sheep, when applied in woolgrease, in an aqueous formulation and in a range of test carriers.

Five formulations containing 10 mg/mL zeta-cypermethrin spiked with 100

Ci [¹⁴C] zeta-cypermethrin were prepared using the following carriers:wool grease (1), 100 g/L emulsifiable concentrate (EC) diluted 1:10 inwater (2), IPM (3), OS (4), and GTCC (5).

Each formulation was applied to the backline of three sheep at 1 mL/5 kgbody weight. Wool was collected from three 12×12-mm squares chosen atrandom, along meridian lines drawn 2, 7.5 and 15 cm down the side ofeach sheep from the backline. The wool samples were collected at 1, 2,4, 8, 11 and 14 days after treatment, and each day's samples werepooled. The clipped areas were also swabbed. At day 14 after treatment,the wool at the site of application was collected and back and perirenalfat samples were collected. The quantity of zeta-cypermethrin in eachsample was measured by liquid scintillation counting.

At most meridians and at most times IPM gave the greatest spread ofzeta-cypermethrin and wool grease the least. In the wool-greaseformulations, the amount of zeta-cypermethrin present continued toincrease with time only at the 2-cm meridian. The quantity ofzeta-cypermethrin measured at all meridians increased with timefollowing IPM. OS and GTCC gave modest spread, but the data did notallow determination of whether spread was continuing. The EC gave littlespread, and movement of zeta-cypermethrin reached a plateau after 2weeks. IPM caused a severe scabbing/crusting of the skin at the site ofapplication.

The experiment was concluded at 2 weeks post-treatment. Wool grease andthe EC formulation gave poor spread, GTCC and OS gave better spread andIPM gave the best spread of zeta-cypermethrin of the vehicles tested.

EXAMPLE 6 Evaluation of Zeta-Cypermethrin in a Variety of Carriers, as aPour-On Formulation for the Control of Bovicola ovis on Sheep

These studies were devised to determine the efficacy ofzeta-cypermethrin (at 2 mg/kg of body weight) in several nonaqueousformulations, and a commercial formulation of deltamethrin, on sheepinfested with a severely synthetic pyrethroid (SP) resistant (Hartley)strain and a moderately SP resistant (Claremont) strain of Bovicolaovis. Some additional studies were undertaken with susceptible andslightly resistant lice to determine whether zeta-cypermethrin was ableto kill lice under optimum conditions.

The nonaqueous formulations tested were: OP/IPM (80:20); 2) GTCC/OP(80:20); 3) WG/C8-10 methyl esters/OP/GTCC [20% WG, 20% esters and 60%of OP/GTCC (80:20)]; 4) 20% WG and 80% GTCC/OP (80:20); and 5) 85%GTCC/OP (80:20) and 15% WG.

Against lice with high and moderate levels of resistance to the SPs, notreatment gave satisfactory lice control. Increasing the volume offormulation applied, but keeping the dose constant, led to a slightincrease in efficacy against the moderately resistant strain.Zeta-cypermethrin eradicated lice on sheep infested with the susceptiblestrain and gave excellent control against a mildly resistant strain.

None of the formulations was significantly superior. The liquidwool-grease-containing formulations produced a very unsightly dirty markin the wool along the treated area that would not be acceptable tofarmers.

The OP/IPM or GTCC/OP formulations appeared to provide a good startingpoint to find a useful zeta-cypermethrin sheep pour-on formulation.

EXAMPLE 7 Evaluation of Zeta-Cypermethrin in a Variety of Carriers, as aPour-On Formulation for the Control of Bovicola ovis on Sheep

Example 6 revealed that zeta-cypermethrin at 2 mg/kg did not giveadequate control against SP-resistant strains of Bovicola ovis, but didcontrol SP-susceptible lice. This study evaluated variouszeta-cypermethrin formulations for their effectiveness in controllingsheep body lice.

Five formulations of zeta-cypermethrin (Treatments 3–9) were compared toa commercial suspension concentrate (SC) formulation ofalphacypermethrin for efficacy to treat moderately SP-resistant lice insheep. The formulations were tested as follows:

Treatment Carrier Dosage (mg/kg)^(a) 1 Control 0 2 Alphacypermethrin SC4 3 OP/IPM (80:20) 2 4 ″ 4 5 GTCC/OP (80:20) 2 6 ″ 4 7 TPM/WG/GTCC(60:20:20) 4 8 OP/IPM/OSU (70:15:15) 4 9 TPM/benzyl alcohol (80:20) 4^(a)The 2 mg/kg dosage was applied at 10 g/L; and the 4 mg/kg dosage wasapplied at 20 g/L.

None of the zeta-cypermethrin formulations tested eradicated lice. TheTPM/benzyl alcohol formulation gave the lowest counts followingtreatment. The OP/IPM at 2 mg/kg and OP/IPM/OSU at 4 mg/kg formulationsgave the next best control. The OP/IPM and GTCC/OP formulations at 4mg/kg were similar in efficacy to that of the alpha-cypermethrinsuspension concentrate formulation.

These results indicated that the TPM/benzyl alcohol or OP/IPM/OSUformulations delivering 4 mg/kg zeta-cypermethrin would control strainsof lice exhibiting zero to low resistance to SPs. Sincezeta-cypermethrin at 2 mg/kg in an inferior formulation (Example 6)eliminated susceptible lice, a TPM/benzyl alcohol or OP/IPM/OSUformulation delivering 4 mg/kg zeta-cypermethrin should give excellentcontrol of SP-susceptible lice.

EXAMPLE 8 Small Scale Trial to Evaluate Spinosad in a Variety ofCarriers, as a Pour-On Formulation for the Control of Bovicola ovis onSheep

In Example 3, lousy sheep housed indoors were treated with 0.4 mg/kgspinosad formulated in OP/IPM/OSU and lice numbers declined by 90%. Whena similar formulation containing 5% oleic was applied to sheep housedoutdoors, efficacy was only 46% (Example 4). This experiment exploredthe effects of an outdoor environment and oleic acid on the efficacy ofa spinosad-containing pour-on formulation against lice.

Spinosad was formulated at 2 g/L in OP/IPM/OSU (70:15:15). Eachformulation was applied at 1 mL/5 kg (or 0.4 mg/kg) to groups of twolouse-infested sheep. There was an outdoor untreated control group. Oneindoor and one outdoor group were treated with OP/IPM/OSU as in Example3. Another outdoor group was treated with OP/IPM/OSU plus 5% oleic acidas in Example 4. A fourth outdoor group was treated with OP/IPM/OSU plus5% oleic acid plus the antioxidant BHT.

The indoor treated sheep had a 77% percent reduction in lice numbersafter 28 days; this result was similar to the effect observed in Example3. The outdoor untreated group had 0% reduction in counts. Both outdoorgroups treated with oleic acid-containing formulations had 40–50%reduction in counts, which was similar to the efficacy seen in Example4. BHT had no effect on efficacy.

EXAMPLE 9 Evaluation of Spinosad in a Variety of Carriers, as a Pour-OnFormulation for the Control of Bovicola ovis on Sheep.

This study assessed the effectiveness of spinosad in an OP/IPM/OSUformulation, a TPM/benzyl alcohol formulation, a suspension concentrateand two other aqueous formulations to control lice outdoors. Anotherpurpose was to confirm that outdoor conditions reduce the efficacy ofany formulation, as compared to indoor conditions. The study alsoassessed the efficacy of UV absorbers/blockers on outdoor efficacy.Merino sheep were used, and the study ran for 6 weeks.

All formulations contained spinosad at 2 mg/kg (1 mL/5 kg body weight).Each of the five formulations was given with a UV blocker present. Inaddition, the OP/IPM/OSU formulation without UV blocker was testedindoors and outdoors.

The nonaqueous formulations contained 1% spinosad and were formulatedand tested as follows:

Group Carrier Ratio Housed 2 OP/IPM/OSU 70:15:15 indoors 3OP/IPM/OSU/zinc oxide/IPP/ 63:13:13:6.6:2.9:1 outdoors BHT 4 OP/IPM/OSU70:15:15 outdoors 5 TPM/benzyl alcohol/zinc 73:18:6.6:2.9:1 outdoorsoxide/IPP/BHT

The OP/IPM/OSU formulation delivering 2 mg/kg spinosad gave 99.96%efficacy indoors; this result was significantly superior to that seenwith the same formulation outdoors with or without a UV blocker. In thegroups housed outdoors, each formulation was similar in effectiveness,although the OP/IPM/OSU formulation was the most effective. UV blockersdid not significantly increase efficacy.

EXAMPLE 10 Evaluation of a Variety of Pour-On Carriers with Ivermectinand Hexaflumuron for the Control of Bovicola ovis on Sheep

Several previous experiments (Examples 3, 4, 6, 8 and 9) have shown thatan OP/IPM/OSU (70:15:15) formulation is both safe for sheep skins and aneffective vehicle to deliver zeta-cypermethrin and spinosad to controllice in sheep. Similarly, carriers based on TPM, such as TPM/benzylalcohol (80:20) are safe and effective. The aim of this study was todemonstrate that these formulations could deliver other classes ofectoparasticides, such as macrocyclic lactones (ivermectin) and insectgrowth regulators (hexaflumuron).

In the study, groups of 4 Merino sheep, housed indoors, were treatedwith ivermectin (40 mg/sheep) or hexaflumuron (600 mg/sheep) inOP/IPM/OSU (70:15:15) or TPM/benzyl alcohol (80:20). Sheep were treatedwith 20 mL of formulation applied to the backline. Six sheep were leftuntreated as controls. Lice were counted every 2 weeks for 12 weeks.

Tables 3 and 4 summarize the results of these studies.

TABLE 3 Lice counts in sheep at day 0 and 14, 28, 42, 56 and 85 daysafter treatment with ivermectin^(a) Group Day 0 Day 14 Day 28 Day 42 Day56 Day 85 Control Mean 618.7 540.0 463.7 611.0 562.8 533.0 Geo Mean608.8 518.4 414.5 586.5 513.8 461.4 Op/IPM/OSU^(b) Mean 706.0 2.3 0.5 00 0 Geo Mean 698.4 1.3 0.3 TPM/Benzyl Alcohol^(c) Mean 606.0 9.5 4.3 0.50.5 0 Geo Mean 564.9 6.3 1.9 0.4 0.3 ^(a)40 mg/sheep ^(b)70:15:15^(c)80:20

TABLE 4 Lice Counts in sheep at day 0 and 14, 28, 42, 56 and 85 daysafter treatment with hexaflumaron^(a) Group Day 0 Day 14 Day 28 Day 42Day 56 Day 85 Control Mean 618.7 540.0 463.7 611.0 562.8 533.0 Geo Mean608.8 518.4 414.5 586.5 513.8 461.4 OP/IPM/OSU^(b) Mean 690.0 86.3 37.814.5 6.0 2.3 Geo Mean 683.1 39.0 8.6 3.3 2.9 1.1 TPM Benzyl Alcohol^(c)Mean 672.3 324.5 110.8 46.8 44.3 16.8 Geo Mean 656.7 266.9 91.0 31.732.4 10.3 ^(a)600 mg/sheep ^(b)70:15:15 ^(c)80:20

EXAMPLE 11 Evaluation of Spinosad in Two Pour-On Formulations andIvermectin as a Pour-On for the Control of Bovicola ovis on Sheep HousedOutdoors

This study evaluated the efficacy of spinosad to eradicate lice in sheepwhen administered in two pour-on vehicles. It also determined the effectof increasing dose or volume on efficacy and whether the incorporationof UV blockers/absorbers increases efficacy. The study further evaluatedthe efficacy of ivermectin to eradicate lice when administered in apour-on formulation to sheep housed outdoors.

Spinosad was administered in OP/IPM/OSU (70:15:15) at 2 and 10 mgspinosad/kg body weight, with and without UV blockers, and applied at 2mL/5 kg of body weight. Ivermectin was administered at 40 mg/sheep in 20mL of OP/IPM/OSU (70:15:15). Spinosad was also administered in anaqueous formulation at 2, 10 and 50 mg/kg without UV blockers andapplied at 1 mL/5 kg. In addition, the 2 mg/kg formulation was appliedat 1 mL/kg. All treatments were applied as a broad band along thebackline. The study ran for 6 weeks.

These results were observed:

-   -   A) Spinosad in OP/IPM/OSU: at 10 mg/kg, with or without UV        blockers, it eradicated lice outdoors; at 2 mg/kg, it gave 85 to        98% efficacy.    -   B) Spinosad in aqueous formulation: at 50 mg/kg, it eradicated        lice; at 10 mg/kg, it gave 98% efficacy; at 2 mg/kg, it gave 74%        efficacy when applied at 1 mL/5 kg and 61% efficacy when applied        at 1 mL/kg.    -   C) Ivermectin in OP/IPM/OSU: at 40 mg/sheep, it gave 96%        efficacy.    -   D) The use of UV blockers or increasing the volume applied did        not increase efficacy.

EXAMPLE 12 Physical Characteristics of Various Formulations

The physical characteristics of various individual solvents and solventcombinations were determined. Table 5 summarizes the results of thesedeterminations.

TABLE 5 Summary of formulation properties and freezing points VehiclePhysical Properties IPM Freeze −2 to −6

C., penetrates + spreads, modifies heavy oils GTCC Freeze −5 to −13

C., safe, solvent/diluent OP or OS Freeze 3 to −4

C., spreads, lubricant OSU Freeze 0 to 15

C., good spreader, wets COI Freeze 0

C., water resistant, good wetter + spreader TPM Freezes <<−15

C. OP/IPM Freezes −4 to −7

C. (80:20) OP/OSU Freezes −7 to −10

C. (80:20) GTCC/IPM Freezes < <10

C. (80:20) TPM/2-octyl Freezes −15

C. dodecanol (80:20) TPM/diacetone Freezes <−15

C. alcohol (80:20)

1. A non-irritant pour-on formulation for control of an externalparasite on an animal of agricultural worth comprising 0.1 to 40% byweight of at least one spinosyn; and a non-irritant topically acceptablecarrier selected from the group consisting of: a) i) tripropylene glycolmethyl ether, and ii) at least one of benzyl alcohol and diacetonealcohol, wherein (i) is present in an amount of at least about 60% wt ofthe carrier; b) i) at least one of octyl palmitate, octyl stearate andglyceryl tri caprylate/caprate, and ii) at least one of dioctylsuccinate, isopropyl myristate, cetearyl octanoate, propylene glycol 2myristyl ether propionate, isopropyl palmitate, isopropyl laurate,isocetyl stearate, oleic acid and methyl oleate, and optionallyincluding iii) at least one of alcohol and propylene glycol, wherein(ii) is present in an amount of up to about 40% wt of the carrier; andc) i) at least one of octyl palmitate, octyl stearate and glyceryl tricaprylate/caprate, and ii) at least one of benzyl alcohol, diacetonealcohol and propylene glycol, wherein (i) is present in an amount of atleast about 60% wt of the carrier.
 2. A formulation of claim 1 whereinthe ratio of tripropylene glycol methyl ether:alcohol is in the range of60–95:40–5.
 3. A formulation of claim 2 wherein the ratio oftripropylene glycol methyl ether:alcohol is 80:20.
 4. A formulation ofclaim 1 wherein the carrier is selected from (b).
 5. A formulation ofclaim 4 wherein (i) is octyl palmitate or octyl stearate.
 6. Aformulation of claim 5 wherein (ii) comprises isopropyl myristate anddioctyl succinate.
 7. A formulation of claim 6 wherein the ratio ofoctyl palmitate:isopropyl myristate:dioctyl succinate is60–90:20–5:20–5.
 8. A formulation of claim 7 wherein the ratio is70:15:15.
 9. A formulation of claim 4 wherein (i) is glyceryl tricaprylate/caprate and (ii) comprises isopropyl myristate and a blend ofisopropyl myristate and cetearyl octanoate.
 10. A formulation of claim 9wherein the ratio of glyceryl tri caprylate/caprate:isopropylmyristate:blend of isopropyl myristate and cetearyl octanoate is in arange of 60–90:20–5:20–5.
 11. A formulation of claim 10 wherein theratio is 70:15:15.
 12. A non-irritant pour-on formulation for control ofan external parasite on an animal of agricultural worth, according toclaim 1, wherein said spinosyn is spinosad.
 13. A method of controllingan external parasite on an animal of agricultural worth, comprisingtopically applying an ectoparasiticidally effective volume of a pour-onformulation of claim
 12. 14. A non-irritant pour-on formulation forcontrol of an external parasite on an animal of agricultural worth,according to claim 2, wherein said spinosyn is spinosad.
 15. A method ofcontrolling an external parasite on an animal of agricultural worth,comprising topically applying an ectoparasiticidally effective volume ofa pour-on formulation of claim
 14. 16. A non-irritant pour-onformulation for control of an external parasite on an animal ofagricultural worth, according to claim 3, wherein said spinosyn isspinosad.
 17. A method of controlling an external parasite on an animalof agricultural worth, comprising topically applying anectoparasiticidally effective volume of a pour-on formulation of claim16.
 18. A non-irritant pour-on formulation for control of an externalparasite on an animal of agricultural worth, according to claim 4,wherein said spinosyn is spinosad.
 19. A method of controlling anexternal parasite on an animal of agricultural worth, comprisingtopically applying an ectoparasiticidally effective volume of a pour-onformulation of claim
 18. 20. A non-irritant pour-on formulation forcontrol of an external parasite on an animal of agricultural worth,according to claim 5, wherein said spinosyn is spinosad.
 21. A method ofcontrolling an external parasite on an animal of agricultural worth,comprising topically applying an ectoparasiticidally effective volume ofa pour-on formulation of claim
 20. 22. A non-irritant pour-onformulation for control of an external parasite on an animal ofagricultural worth, according to claim 6, wherein said spinosyn isspinosad.
 23. A method of controlling an external parasite on an animalof agricultural worth, comprising topically applying anectoparasiticidally effective volume of a pour-on formulation of claim22.
 24. A non-irritant pour-on formulation for control of an externalparasite on an animal of agricultural worth, according to claim 7,wherein said spinosyn is spinosad.
 25. A method of controlling anexternal parasite on an animal of agricultural worth, comprisingtopically applying an ectoparasiticidally effective volume of a pour-onformulation of claim
 24. 26. A non-irritant pour-on formulation forcontrol of an external parasite on an animal of agricultural worth,according to claim 8, wherein said spinosyn is spinosad.
 27. A method ofcontrolling an external parasite on an animal of agricultural worth,comprising topically applying an ectoparasiticidally effective volume ofa pour-on formulation of claim
 26. 28. A non-irritant pour-onformulation for control of an external parasite on an animal ofagricultural worth, according to claim 9, wherein said spinosyn isspinosad.
 29. A method of controlling an external parasite on an animalof agricultural worth, comprising topically applying anectoparasiticidally effective volume of a pour-on formulation of claim28.
 30. A non-irritant pour-on formulation for control of an externalparasite on an animal of agricultural worth, according to claim 10,wherein said spinosyn is spinosad.
 31. A method of controlling anexternal parasite on an animal of agricultural worth, comprisingtopically applying an ectoparasiticidally effective volume of a pour-onformulation of claim
 30. 32. A non-irritant pour-on formulation forcontrol of an external parasite on an animal of agricultural worth,according to claim 11, wherein said spinosyn is spinosad.
 33. A methodof controlling an external parasite on an animal of agricultural worth,comprising topically applying an ectoparasiticidally effective volume ofa pour-on formulation of claim 32.